Genetic integration of pRB and Hippo tumor suppressor pathways

描述(申请人提供)：视网膜母细胞瘤(PRB)途径是一个关键的肿瘤抑制途径。它在正常发育中起着关键作用，而它的功能失活在大多数癌症中都会发生。E2F因子家族是pRB的关键下游靶点之一，失控的E2F活性被认为促进了肿瘤细胞的增殖。相比之下，人们对河马肿瘤抑制新途径知之甚少。然而，最近在苍蝇和哺乳动物中的研究表明，河马途径控制着组织的动态平衡，而它的放松调控导致了肿瘤的发生，从而强调了它在影响恶性状态中的重要作用。利用果蝇模型系统，我们发现在限制细胞增殖和维持终末分化状态方面，河马途径与pRb途径具有很强的协同作用。这两条通路的联合失活会导致不适当的增殖，令人惊讶的是，还会导致广泛的去分化。重要的是，串扰的这两个方面是相互独立的，反映了PRB通路的不同功能。该方案中的实验将使用方法和新开发的工具的组合来确定两条途径之间合作的细胞机制，并在体内测试这些机制的重要性。在目标1中，我们将破译河马和Rb通路在限制细胞增殖方面依赖于E2F的合作方面。在目标2中，我们将研究这两条通路是如何整合以维持分化状态的。这一知识最终可能形成操纵这些途径的基础，并可能有助于设计治疗癌症的新的抗癌疗法。

DESCRIPTION (provided by applicant): The Retinoblastoma (pRB) pathway is a key tumor-suppressor pathway. It plays a pivotal role in normal development while its functional inactivation occurs in most cancers. The family of E2F factors is one of the key downstream targets of pRB and deregulated E2F activity is thought to drive proliferation in tumor cells. In contrast, less is known about novel Hippo tumor-suppressor pathway. However, recent studies in flies and in mammals suggested that Hippo pathway controls tissue homeostasis while its deregulation leads to tumorigenesis, thus, underscoring its important role in influencing the malignant state. Using a Drosophila model system, we have discovered that Hippo pathway strongly cooperates with pRB pathway in limiting cell proliferation and in maintenance of the state of terminal differentiation. Combined inactivation of both pathways gives rise to inappropriate proliferation and, surprisingly, to extensive dedifferentiation. Importantly, these two facets of a crosstalk are independent of each other and reflect distinct functions of the pRB pathway. Experiments in this proposal will use a combination of approaches and newly developed tools to define the cellular mechanisms underlying cooperation between the two pathways and to test the importance of these mechanisms in vivo. In Aim 1, we will decipher an E2F-dependent aspect of cooperation between Hippo and RB pathways in limiting cell proliferation. In Aim 2 we will investigate how the two pathways are integrated to maintain the differentiated state. This knowledge could eventually form a basis for manipulating the pathways and may help in designing new anticancer therapies for treating cancers.